May 2021 – Hematopathology
A man in his 70s presented with persistent leukocytosis, thrombocytopenia, anemia, and splenomegaly. The findings of the laboratory workup are outlined in the table and figure below.
What is the best diagnosis?
- Chronic neutrophilic leukemia
- Chronic myelomonocytic leukemia
- Chronic myeloid leukemia, BCR-ABL1-positive
- Atypical chronic myeloid leukemia, BCR-ABL1-negative
The correct answer is ...
The correct answer is: Atypical chronic myeloid leukemia, BCR-ABL1-negative.
Atypical chronic myeloid leukemia (CML), BCR-ABL1-negative, is categorized under myelodysplastic/myeloproliferative neoplasms in the current World Health Organization (WHO) classification. The typical clinical presentation is a combination of leukocytosis, anemia, thrombocytopenia, and splenomegaly in the seventh or eighth decade of life. It is characterized by an aggressive clinical course, with leukemic transformation in a subset of patients.
On microscopic examination, the peripheral blood leukocytosis is due to an increase of neutrophils as well as granulocyte precursors (promyelocytes, myelocytes, and metamyelocytes) that comprise ≥10% of the leukocytes. By definition, blasts constitute less than 20% of peripheral blood and bone marrow cellularity. Myelodysplasia is most prominent in the granulocytic lineage, manifesting as hypersegmented nuclei with clumped chromatin or cytoplasmic hypogranularity (subtle but present in this case) among other morphologies. However, dyserythropoiesis and dysmegakaryopoiesis also may be seen. The latter is exemplified in this case by a mixture of hypogranular and large/oblong platelets, indicated by the blue arrows in the figure, in addition to the small and hypolobated megakaryocytes and megakaryocytes with abnormally disjointed nuclei in the patient’s bone marrow. The bone marrow is typically hypercellular, with an increased myeloid-to-erythroid ratio frequently exceeding 10:1.
Per WHO diagnostic criteria, BCR-ABL1 fusion is not present. Similarly, cases with rearrangements of PDGFRA, PDGFRB or FGFR1, or PCM1-JAK2 are not included within the category of atypical CML, BCR-ABL1-negative. In this case, fluorescence in situ hybridization was utilized to rule out CHIC2 deletion as a surrogate for the cytogenetically cryptic FIP1L1-PDGFRA fusion. The most common karyotypic abnormalities in this entity are trisomy 8 and deletion 20q.
In contrast to atypical CML, BCR-ABL1-negative; CML, BCR-ABL1-positive is a myeloproliferative neoplasm characterized by t(9;22)(q34.1;q11.2), leading to the formation of the Philadelphia chromosome. The latter entity is relatively more common and lacks significant granulocytic dysplasia. Chronic neutrophilic leukemia is another myeloproliferative neoplasm that is devoid of significant granulocytic dysplasia. It is characterized by <10% immature myeloid cells in the peripheral blood, unlike atypical CML, BCR-ABL1-negative. Chronic myelomonocytic leukemia (CMML) is another condition in the differential diagnosis. Persistent monocytosis in the peripheral blood (≥1 x 109/L, comprising 10% or more of the leukocytes) is an important feature of CMML, and is used to distinguish it from CML, BCR-ABL1-negative.
- Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2017.
- Schwartz LC, Mascarenhas J. Current and evolving understanding of atypical chronic myeloid leukemia. Blood Rev. 2019;33:74-81.
- Sadigh S, Hasserjian RP, Hobbs G. Distinguishing atypical chronic myeloid leukemia from other Philadelphia-negative chronic myeloproliferative neoplasms. Curr Opin Hematol. 2020;27:122-127.
Burak Tekin, M.D.
Resident, Anatomic and Clinical Pathology
Adam Wood, D.O., M.S.
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science